Processes for the preparation of N-methyl-L-alanine derivatives from dithioalkanoic acid intermediates and N-methyl-L-alanine have been reported in U.S. Pat. No. 5,208,020. The compounds are useful for linking cytotoxic maytansinoids to cell-binding agents such as antibodies. Antibody/maytansinoid complexes are useful as tumor-activated pro-drugs.
For example, the multi-step synthesis of N-methyl-N-(3-methyldithio-propanoyl)-L-alanine has been disclosed. First, 3-methyldithiopropanoic acid was prepared by adding methyl methanethiosulfonate in ethanol to a solution of 3-mercaptopropanoic acid in water. After extraction, washing and concentration, the 3-methyldithiopropanoic acid was isolated by distillation. Isobutylchloroformate and triethylamine were added to the 3-methyldithiopropanoic acid in THF to form the corresponding mixed anhydride as intermediate. Subsequently, a mixture of N-methyl-L-alanine and triethylamine in water was added. After extraction, oncentration and chromatography, a 34% yield of N-methyl-N-(3-methyldithio-propanoyl)-L-alanine was obtained.
A major shortcoming of the prior art processes is the necessity of two chromatography steps to remove side products from the desired reaction products. Further, the use of isobutylchloroformate in the reaction scheme allows for racemization which leads to a final product containing the undesired D-enantiomer. Thus, there is a need in the art for improved methods to prepare N-methyl-L-alanine derivatives with an optical purity >95% enantiomeric excess (ee) where the intermediates are more stable, resulting in less undesired side products.